Catalytic Asymmetric Synthesis of All Possible Stereoisomers of 2,3,4,6-Tetradeoxy-4-Aminohexopyranosides

Article abstract of DOI:10.1002/adsc.201800029

We recently developed a divergent strategy for the synthesis of all eight possible 2,3,6-trideoxyhexopyranosides with three stereogenic centers. However, the diastereoselectivity for one of the three stereogenic centers was low and it was not controlled b

Full text of DOI:10.1002/adsc.201800029

Title: Catalytic Asymmetric Synthesis of All Possible Stereoisomers of
2,3,4,6-Tetradeoxy-4-aminohexopyranosides
Authors: Zhongpeng Zhu, Daniel Glazier, Daoshan Yang, and Weiping
Tang
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201800029
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10.1002/adsc.201800029
Advanced Synthesis & Catalysis
UPDATE
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Catalytic Asymmetric Synthesis of All Possible Stereoisomers of
2,3,4,6-Tetradeoxy-4-aminohexopyranosides
Zhongpeng Zhu,a,b Daniel A. Glazier,a,c Daoshan Yang,a,d and Weiping Tang*a,c
a
School of Pharmacy, University of Wisconsin-Madison, Madison, WI 53705, USA
Phone: (608) 890-1846, Fax: (608) 262-5345, Email: wtang@pharmacy.wisc.edu
School of Chemical Sciences, University of Chinese Academy of Sciences, Beijing, P. R. of China
Department of Chemistry, University of Wisconsin-Madison, Madison, WI 53705, USA
School of Chemistry and Chemical Engineering, Qufu Normal University, Qufu 273165, P. R. of China.
b
c
d
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.
ossamine and its analogues were also realized from
Abstract. We recently developed a divergent strategy for the
synthesis of all eight possible
2,3,6- chiral starting materials.[8]
trideoxyhexopyranosides with three stereogenic centers.
However, the diastereoselectivity for one of the three
stereogenic centers was low and it was not controlled by
catalysts. In this update, we described a systematic method
for the first catalytic asymmetric synthesis of all eight
possible 2,3,6-trideoxyhexopyranoside and all eight possible
2,3,4,6-tetradeoxy-4-aminohexopyranosides. The products
derived from this strategy include the glycone of natural
products grecocycline A, spinosyn A, and ossamycin. All
three stereogenic centers in each product was controlled by
a pair of chiral catalysts. The key to the success is the
application of our recently developed dynamic kinetic
stereodivergent acylation of Achmatowicz rearrangement
products and chiral catalyst-directed reduction. Simple
dimethylation of the 2,3,4,6-tetradeoxy-4-amino sugars
afforded derivatives of naturally occurring β-D-
forosaminide and β-L-ossaminide.
Keywords: deoxy sugars; amino sugars; asymmetric
catalysis; carbohydrates, divergent
Deoxyamino sugars are frequently found in natural
products, such as aminoglycosides, macrolides, and
anthracyclines, and the sugar units are often essential
to the pharmacological activities of the natural
products.[1] Some examples of 2,3,4,6-tetradeoxy-4-
aminopyranoside-containing natural products are
shown in Figure 1. These natural products have a
broad range of biological activities, such as cytotoxic
agent grecocycline A,[2] protein tyrosine phosphatase
1B inhibitor grecocycline B,[2] insecticide spinosyns,[3]
and oxidative phosphorylation inhibitor ossamycin.[4]
Derivatives of griseusins also have potent antibiotic,
antifungal, and anticancer activities.[5]
Figure 1. Natural products containing 2,3,4,6-tetradeoxy-4-
amino sugars
Not surprisingly, significant efforts have been
devoted to the synthesis of deoxyamino sugars.[6] For
example, both O-ethyl ossaminide and ossamine were
synthesized from glucose or its derivatives in over 10
Forosamine is a diastereoisomeric isomer of
ossamine. Both α/β and D/L forms of forosamines are
found in natural products as shown in Figure 1. Since
7]
steps.[4c, More recent efforts on the synthesis of
1
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10.1002/adsc.201800029
Advanced Synthesis & Catalysis
the structure and stereochemistry of forosamine was
discovered in 1966 a number of synthetic routes have
been developed.[7a,9] Two de novo syntheses of
forosamine involved either the epoxidation of sorbic
acid followed by kinetic resolution of the resulting
acid or chemoenzymatic resolution of the epoxide
derived from methyl sorbate.[10] In Evans’s synthesis
of lepicidin A, the L-forosamine glycone was prepared
from an oxazolidinone chiral auxiliary in nearly ten
steps.[11] Racemic forosamine was synthesized by
Tietze’s group via a domino Knoevenagel-Hetero-
Diels-Alder reaction and resolved by chiral HPLC.[12]
A Ru-catalyzed cycloisomerization was employed by
Merck for the synthesis of L-forosamine from an
acyclic chiral amino alcohol.[13] Dai’s group recently
accomplished a concise synthesis of spinosyn A and
observed a 1:1 β/α stereoselectivity.[14] Prior to Dai’s
work, the undesired α-isomer was the major product[11,
Scheme 1. Previous Strategy for Divergent Synthesis of All
Possible Stereoisomers of 2,3,6-trideoxypyranosides
Optically pure lactol 1 (98% ee) could be prepared
in two steps on the gram scale from 2-acetylfuran via
catalytic asymmetric reduction mediated by
[Cp*RhCl]2/(R, R)-Ts-DPEN L1 followed by an
Achmatowicz rearrangement (Scheme 2).[17] Our
15]
with the exception of Roush’s strategy.[16] In
Roush’s synthesis of spinosyn A, a deoxyamino sugar
with a C2-OAc directing group was introduced to the
macrocyclic aglycone with β-selectivity by Schmidt
glycosylation, and the C2-OAc was later removed by
deoxygenation.[16] The synthesis of Roush’s glycosyl
donor, however, requires more than ten steps and
another five steps are necessary for the removal of the
C2-OAc group after the glycosylation.
We herein report a systematic strategy for the
catalytic asymmetric synthesis of all eight possible
2,3,4,6-tetradeoxy-4-aminohexopyranosides,
including the glycone of natural products grecocycline
A and B, spinosyn A, and ossamycin.
We previously reported a divergent strategy for the
synthesis of all possible stereoisomers of 2,3,6-
trideoxypyranosides (Scheme 1).[17] Lactol 1 derived
from Achmatowicz rearrangement[18] was converted to
carbonates 2 and 3 under two different conditions and
separated by column chromatography according to
O’Doherty’s protocol.[19] Although the overall
efficiency is very high and the palladium-catalyzed
glycosidation offered complete control for the α- and
β-stereoselectivity on the anomeric position,[20] the
stereoselectivity for the conversion of 1 to 2a or 2b
remained to be an unsolved problem. Recently, we[21]
and others[22] reported an effective method for the
dynamic kinetic stereoselective acylation of lactols
derived from an Achmatowicz rearrangement[18] using
chiral organocatalysts. We envision that this strategy
will provide a solution for the above problem and
allow us to access various deoxy and deoxyamino
sugars highly stereoselectively.
chiral
catalyst-directed
dynamic
kinetic
diastereoselective acylation method provided ester
products 3a and 3b from 1 using (R)- and (S)-BTM
catalysts, respectively.[21a] These esters can be
converted to the deoxyglycosides 4a and 4b by Pd-
catalyzed allylic alkylation.[21a] Their enantiomers,
ent-4a and ent-4b, can be prepared from ent-1 with
similar efficiency and stereoselectivity. Using
[Cp*RhCl]2 and a pair of chiral ligands L1 and L2, we
have demonstrated that a highly diastereoselective
reduction of 4a, 4b, ent-4a, and ent-4b can be
realized.[17] All possible stereoisomers of 2,3,6-
trideoxy-hexopyranosides (5a-5d and ent-5a-5d) can
thus be prepared by the choice of two pairs of catalysts
- reduction of 2-acetylfuran or enones directed by
Rh(III)/L1 or L2 catalysts and esterification of lactols
directed by (R)- or (S)-BTM catalysts. This catalytic
and divergent strategy can be applied to the synthesis
of numerous bioactive natural products[23] containing
amicetopyranosides 5a, 5d, ent-5a, and ent-5d or
rhodinopyranoside 5b, 5c, ent-5b, and ent-5c in either
α/β or D/L forms.
To further examine the scope of this strategy, we
also prepared dihydropyranone 6a efficiently and
stereoselectively
using
secondary
alcohol
cyclohexanol as the nucleophile for the Pd-catalyzed
allylic alkylation. The reduction of 6a was highly
diastereoselective and yielded 2,3,6-trideoxy
hexapyranoside 6b.
Having all eight stereoisomers 5a-5d and ent-5a-5d
in hand, we then turned our attention to the synthesis
of their corresponding deoxyamino sugars by
introducing the amino group through a Mitsunobu
reaction and subsequent reduction (Scheme 3). All
eight 2,3,4,6-tetradeoxy-4-aminohexopyranosides 8a-
8d and ent-8a-8d were prepared in high yields.
Deoxyamino sugar 8e bearing a secondary alcohol was
also prepared by the same sequence in a good overall
yield.
2
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10.1002/adsc.201800029
Advanced Synthesis & Catalysis
Scheme 2. Dynamic Kinetic Stereoselective Acylation of
Lactols Followed by Pd-catalyzed Stereospecific Allylic
Alkylation and Chiral Catalyst-Directed Reduction
Scheme 3. Preparation of all possible 2,3,4,6-tetradeoxy-4-
aminohexopyranosides
Among the deoxyamino glycosides in Scheme 3,
ent-8a is the glycone in natural product grecocyclines
A and B. To further demonstrate the utility of this
strategy, we next prepared O-benzyl-β-D-
forosaminide 9，O-benzyl-β-L-ossaminide 10, and O-
benzyl-α-D-forosaminide 11 by introducing the N,N-
dimethyl group via reductive amination following a
known protocol (Scheme 3).[24] Deoxyamino glycoside
9 and 10 are the glycones in natural products spinosyn
A and ossamycin.
Experimental Section
Procedure for the synthesis of 8a from 5a:
To a solution of compound 5a (62 mg, 0.3 mmol, 1 equiv)
in THF (15–20 mL per mmol) was added PPh3 (236 mg, 0.9
o
mmol, 3 equiv) at -20 C. To this mixture was added a
solution of DIAD (152 mg, 0.75 mmol, 2.5 equiv) and
DPPA (207 mg, 0.75 mmol, 2.5 equiv) in THF (5–7 mL per
mmol) at -20 oC. The reaction mixture was then allowed to
warm to room temperature and monitored by TLC (~12 h).
The resulting solution was then diluted with Et2O, washed
with brine, dried over Na2SO4, filtered, and concentrated to
yield the crude product, which was purified by column
chromatography to give product 7a (57 mg, 0.23 mmol,
84%) as a colorless oil.
In summary, we have developed a catalytic
asymmetric synthesis of all eight possible
stereoisomers
of
2,3,4,6-tetradeoxy-4-
aminopyranosides in 7 steps starting from 2-
acetylfuran with approximately a 20% overall yield for
each isomer. The three stereogenic centers are dictated
by two pairs of chiral catalysts. The synthesis of
ossaminide and forosaminide were also realized
efficiently. We anticipate that this systematic synthetic
strategy can be extended to the divergent synthesis of
other aminoglycosides and their analogues and applied
to the synthesis of complex natural products with a
high level of control for each stereogenic center.
To a solution of azide 7a (42 mg, 0.17 mmol, 1.0 equiv) in
THF (30–40 mL per mmol) and H2O (183 mg) was added
PPh3 (2.5 equiv), and the reaction was stirred under reflux
and monitored by TLC (~10 h). After evaporation, the
residue was purified by column chromatography to yield
compound 8a (33.8 mg, 0.15 mmol, 90%) as a colorless oil.
3
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10.1002/adsc.201800029
Advanced Synthesis & Catalysis
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We thank the University of Wisconsin-Madison for funding. Z. Zhu
thanks the University of Chinese Academy of Sciences for financial
support (UCAS Joint PhD Training Program, UCAS[2015]37) of a
visiting student position at the University of Wisconsin–Madison.
This study made use of the Medicinal Chemistry Center at UW-
Madison instrumentation funded by the UW School of Pharmacy.
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Advanced Synthesis & Catalysis
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5
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10.1002/adsc.201800029
Advanced Synthesis & Catalysis
UPDATE
Catalytic Asymmetric Synthesis of All Possible
Stereoisomers of 2,3,4,6-Tetradeoxy-4-
aminohexopyranosides
Adv. Synth. Catal. Year, Volume, Page – Page
Zhongpeng Zhu, Daniel A. Glazier, Daoshan Yang,
and Weiping Tang*
6
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